What is the preferred first‑line systemic therapy for a patient with lung adenocarcinoma that harbors a ROS1 rearrangement?

First-Line Treatment for ROS1-Positive Lung Adenocarcinoma

For treatment-naïve patients with ROS1-rearranged lung adenocarcinoma, crizotinib, entrectinib, or repotrectinib are the preferred first-line targeted therapies, with crizotinib being the most established option demonstrating 70-80% response rates and median progression-free survival of 19.2 months. 1, 2

Preferred First-Line Options

The NCCN guidelines designate three agents as preferred first-line therapies for ROS1-positive metastatic NSCLC 1, 2:

Crizotinib (Most Established)

• Crizotinib remains the gold standard first-line option based on FDA approval and the most robust clinical trial data 1
• Achieves objective response rates of 70-80%, including complete responses in some patients 1
• The PROFILE 1001 phase I study demonstrated a 72% objective response rate with median progression-free survival of 19.2 months and median overall survival of 51.4 months 1
• The EUCROSS phase II study confirmed a 70% objective response rate with median PFS of 20 months 1
• An Asian phase II trial in 127 patients showed 71.7% response rate with median PFS of 15.9 months 1
• Crizotinib is an oral tyrosine kinase inhibitor targeting ALK, ROS1, and MET 1

Entrectinib (Superior CNS Penetration)

• Entrectinib is FDA-approved for first-line treatment and offers critical advantages for patients with brain metastases 1, 2, 3
• Pooled analysis from three trials (STARTRK-1, STARTRK-2, ALKA-372-001) showed 77% objective response rate in 53 treatment-naïve ROS1-positive patients 1
• Intracranial response rate was 55% among 20 patients with baseline CNS metastases, including 4 complete responses 1
• The key advantage is superior CNS penetration compared to crizotinib, making it particularly valuable for patients with brain involvement 1, 2
• The main limitation is higher toxicity: grade 3-4 adverse events occurred in 34% of patients, with serious adverse events including nervous system and cardiac disorders 1
• Entrectinib inhibits ROS1, ALK, and TRK kinases 1, 3

Repotrectinib (Newest Option)

• Repotrectinib is FDA-approved as a preferred first-line option, particularly for patients with CNS involvement 1, 2
• The TRIDENT-1 trial demonstrated 79% confirmed objective response rate in 71 treatment-naïve ROS1-positive patients 1
• Repotrectinib is a next-generation ROS1, TRK, and ALK inhibitor 1

Alternative First-Line Option

Ceritinib (Less Preferred)

• Ceritinib may be considered in crizotinib-naïve patients but is not a preferred option 1
• A phase II trial showed 62% objective response rate with median PFS of 19.3 months in crizotinib-naïve patients 1
• Ceritinib is an oral TKI inhibiting ROS1 and IGF-1 receptor 1

Clinical Decision Algorithm

Choose your first-line ROS1 inhibitor based on:

1. Presence of brain metastases: If CNS involvement is present or suspected, prioritize entrectinib or repotrectinib over crizotinib due to superior CNS penetration 1, 2

2. Toxicity tolerance: If patient has cardiac risk factors or concerns about nervous system adverse events, crizotinib may be preferred over entrectinib due to lower toxicity profile 1

3. Drug availability and access: Crizotinib has the longest track record and may have better insurance coverage in some settings 1

Critical Testing Requirements

• ROS1 testing must be performed using FISH or FDA-approved tests on tumor tissue before initiating therapy 2, 4
• Plasma testing is only appropriate when tumor tissue is unavailable 2
• ROS1 rearrangements occur in approximately 1-2% of NSCLC patients, more commonly in younger patients, women, adenocarcinoma histology, and never-smokers 1, 4
• Next-generation sequencing can detect ROS1 rearrangements if the platform has been appropriately validated 1, 5

Important Pitfalls to Avoid

• Do not use alectinib or other ALK-specific inhibitors for ROS1-positive disease - they are not effective despite structural similarities between ALK and ROS1 1
• Do not delay treatment waiting for additional molecular testing once ROS1 rearrangement is confirmed 4
• Avoid platinum-based chemotherapy as first-line when a ROS1 rearrangement is identified - targeted therapy is vastly superior 1
• In patients with biomarkers who have progressed on targeted therapy, immunotherapy appears less effective regardless of PD-L1 expression 1, 4

Subsequent Therapy Considerations

When patients progress on first-line ROS1 TKI therapy 1, 2:

• For progression after crizotinib or ceritinib: repotrectinib or lorlatinib are recommended targeted options 2
• For CNS progression: entrectinib, repotrectinib, or lorlatinib with consideration of stereotactic radiosurgery 2
• Platinum-based chemotherapy (carboplatin/pemetrexed for nonsquamous) may be considered 1
• Strongly consider rebiopsy with tissue-based testing at progression to identify resistance mechanisms 2